tbuckley/cabot-search huggingface dataset:
Anlotinib for the treatment of locally advanced or metastatic pheochromocytoma and paraganglioma: A retrospective study.
Authors: Rui Tian, Xiaochen Yao, Jun Wang, Jingjing Fu, Jieping Song, Liang Shi, Fei Yu, Pengjun Zhang, Yudan Ni, Feng Wang
Journal: Journal of Clinical Oncology (2022)

e16209 Background: Pheochromocytomas (PCC) and paragangliomas (PGL) are rare hyper-vascular neuroendocrine tumors derived from the adrenal medulla and paraganglia, respectively. In previous studies, the overall survival at 5 years for patients (pts) with metastatic disease was only 50% to 60% after the diagnosis of metastases. Anlotinib is a novel multikinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study investigated the efficacy and safety of anlotinib monotherapy or in combination with other therapies in treating locally advanced or metastatic (LA/M) PCC and PGL. Methods: Pts with histologically or cytologically confirmed unresectable or progressive LA/M PCC or LA/M PGL were enrolled from March 2020 to October 2021. The inclusion criteria contained: (a) age 18 or older, (b) ECOG performance status 0–2, (c) adequate organ and marrow function. Eligible pts received anlotinib monotherapy or in combination with peptide receptor radionuclide therapy (PRRT) or 131 I-MIBG. Anotinib was given orally 12 mg once daily (d1-d14, q3w) until the disease progression or the intolerable toxicities. Tumor response was assessed according to RECIST1.1. Results: 35 pts were enrolled (Table) and 25 were assessed for tumor response. Among them, 17 received anlotinib alone, others were treated with the combination regimen, including 6 with PRRT, and 2 with 131 I-MIBG respectively. At the data cut-off date on January 15th, 2022, 4 pts progressed and 1 died. The median duration of treatment was 8.5 months. 10 pts (40%) achieved partial response (PR) and the stable disease (SD) was observed in 13 pts (52%). The objective response rate (ORR) for 25 pts was 40% and the disease control rate (DCR) was 92%. For pts with PCC and PGL, the ORR was 33.3% and 46.2%, respectively. All pts were assessed for safety. The most common adverse events (AEs) included: malaise (23 pts, 65.7%), palmar-plantar erythrodysesthesia syndrome (PPE) (23 pts, 65.7%), hypertension (22 pts, 62.9%) and oropharyngeal pain (17 pts, 48.6%). The most common grade 3 or worse AEs were hypertension (15 pts) and PPE (4 pts), which were claimed tolerable by the pts. Conclusions: This single-center retrospective study indicated that anlotinib monotherapy or in combination with radionuclide therapy showed promising efficacy and favourable safety profile in the treatment of LA/M PCC and PGL, which is worthy of further exploration.[Table: see text]
NuRD complex recruitment to Thpok mediates CD4 <sup>+</sup> T cell lineage differentiation
Authors: Yayi Gao, Monica Zamisch, Melanie Vacchio, Laura Chopp, Thomas Ciucci, Elliott L. Paine, Gaelyn C. Lyons, Jia Nie, Qi Xiao, Ekaterina Zvezdova, Paul E. Love, Charles R. Vinson, Lisa M. Jenkins, Rémy Bosselut
Journal: Science Immunology (2022)

Although BTB–zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4 + T cell development and the expression of most CD4 + and CD8 + lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a critical Thpok cofactor. Using mass spectrometry and coimmunoprecipitation in primary T cells, we show that Thpok binds NuRD components independently of DNA association. We locate three amino acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions. Conversely, a chimeric protein merging the NuRD component Mta2 to a BTB-less version of Thpok supports CD4 + T cell development, indicating that NuRD recruitment recapitulates the functions of the Thpok BTB domain. We found that NuRD mediates Thpok repression of CD8 + lineage genes, including the transcription factor Runx3 , but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-ZF factors, which control the differentiation of most hematopoietic subsets.
Structure-based prediction of neoantigens paired with T cell receptors on pre-existing CD8+ tumor-infiltrating lymphocytes.
Authors: Bo Ryeong Lee, Sungsik Kim, Sung-min Kim, Keunchil Park, Woong-Yang Park
Journal: Journal of Clinical Oncology (2022)

e14583 Background: Tumor neoantigens have ability to expand tumor-specific T cell immunity, which could be boosted by anti-PD-1 immunotherapy. Therapeutically relevant neoantigens should be presented on patient HLAs and recognized by tumor-reactive T cells. Despite tumor-infiltrating lymphocytes (TILs) have enriched tumor-reactive T cell populations, most tumor-specific TILs exhibit exhausted phenotype and have limitations to in vitro screening. Here, we developed in silico structure-based prediction of neoantigen discovery pipeline by pairing with T cell receptors (TCRs) on pre-existing CD8+ exhausted tumor-infiltrating lymphocytes. Methods: Tumor resections from patients with liver, stomach, colorectal, and lung cancers are subject to whole exome and transcriptome. In addition, TILs from the patients are subject to scRNA/TCRseq to select TCRs of exhausted T cells, which are mostly thought to have tumor-reactivity. Neoantigen epitopes are prioritized from our in silico pipeline including HLA binding and TCR-peptide-HLA structure-based pairing score. To evaluate the immunogenicity of selected neoantigens, the neoantigens are tested for in vitro IFNg ELISPOT assay using peripheral blood mononuclear cells (PBMCs) from the same patients, which sensitively detects antigen-experienced T cells. Results: For 5 patients with T cell-reactive neoantigens, among 23 neoantigens selected by our in silico pipeline and tested in vitro, 10 neoantigens showed positive pre-existing T cell responses by matched patients. Then, we analyzed gene expression profiles of TILs paired in silico with in vitro T cell response-positive or negative neoantigens (pTILs and nTILs, respectively) combined with TILs from 23 solid cancer patients. Interestingly, pTILs were mostly mapped to the clusters which highly expressed markers of exhaustion and cytotoxicity, while nTILs showed random distribution across all the clusters. Conclusions: Neoantigen prediction using structure-based pairing of neoantigens and phenotype-selected TILs showed promising potential to better select therapeutically-relevant cancer vaccines. This data supports further investigation of our in silico pipeline into more patient samples and preclinical studies in mouse tumor models.
Regional subgroup analysis of the phase 3 TOPAZ-1 study of durvalumab (D) plus gemcitabine and cisplatin (GC) in advanced biliary tract cancer (BTC).
Authors: Arndt Vogel, Li-Tzong Chen, Aiwu Ruth He, Jin Won Kim, Ming-Huang Chen, Mairead Geraldine McNamara, Satoshi Shimizu, Roopinder Gillmore, Felipe Rey, Hyosung Kim, Julia Xiong, Mallory Makowsky, Nana Rokutanda, Gordon Cohen, Do-Youn Oh
Journal: Journal of Clinical Oncology (2022)

4075 Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of D + GC as first-line treatment for patients (pts) with advanced BTC. D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC (Oh D-Y, et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Methods: A pre-specified subgroup analysis was performed for efficacy outcomes including OS for pts enrolled in Asia (China, Hong Kong, India, Japan, South Korea, Taiwan, Thailand) or the rest of the world (RoW; Europe [Bulgaria, France, Italy, Poland, Russia, Turkey, United Kingdom], North America [NA; USA], and South America [SA; Argentina, Chile]). Post hoc country level analyses were also performed to better characterize outcomes in different countries and regions. Pts with BTC were randomized 1:1 to D (1500 mg once every 3 weeks [Q3W]) or PBO, + G (1000 mg/m 2 ) and C (25 mg/m 2 ) on Days 1 and 8, Q3W, for up to 8 cycles, followed by D (1500 mg Q4W) or PBO monotherapy until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from a Cox proportional hazards model. Results: Pt numbers were balanced across regions (Asia, n=374 [54.6%]; RoW, n=311 [45.4%]). Baseline characteristics were balanced between regions with the exception of modest differences in important pre-defined prognostic factors, including disease status: recurrent disease (Asia 23%; RoW 14.5%), ECOG performance status 1 (Asia 59.1%; RoW 41.2%), and metastatic disease (Asia 89.3%; RoW 82%). In the PBO arm, more pts in Asia received subsequent anti-cancer therapies than pts in RoW (53.6% vs 43.9%). Median duration of follow-up in censored pts was about 2 months (mo) longer in Asia versus RoW (14.8 vs 13.0 mo in D + GC; 13.8 vs 12.1 mo in PBO + GC). Regional level analysis (Table) showed outcomes were similar and approximated the overall population for Asia, Europe, and NA. Grade 3/4 adverse events were similar for Asia (D + GC 78.5%; PBO + GC 78.6%) and RoW (D + GC 72.7%; PBO + GC 76.7%). Conclusions: Despite some regional differences in prognostic characteristics, OS trends favored D + GC versus PBO + GC for pts enrolled in both Asia and RoW, supporting the use of D + GC as a potential new treatment option for all pts with BTC. Country-specific and regional outcomes continue to be explored. Clinical trial information: NCT03875235. [Table: see text]
Bone-targeting agent utilization among lung cancer patients with bone metastasis in Taiwan.
Authors: Jin-Yuan Shih, Tom Wei-Wu Chen, Hui-Min Diana Lin, Yea-Harn Yang, Wei-Ju Chen, K. Arnold Chan
Journal: Journal of Clinical Oncology (2022)

e24111 Background: Bone is a common metastatic site among patients with advanced lung cancer. With new treatments available to improve survival of lung cancer and in all likelihood to change the natural history of disease, the diagnosis and management of bone metastasis (BM) may be of increasing clinical relevance. This study aimed to describe the management of BM using bone targeting agents (BTA) among lung cancer patients in Taiwan. Methods: A retrospective cohort of lung cancer patients with BM from 2004 through 2016 was identified using Taiwan National Health Insurance (NHI) data and Taiwan Cancer Registry. Diagnosis codes of International Classification of Disease 9 th revision (ICD-9: 198.5) and ICD-10 (C79.51 and C78.03) were used to define BM. Patients were followed from the time of BM diagnosis till death or the end of study period (2017/12/31). We ascertained demographic information and BTA use among these patients. Two classes of BTAs were included: bisphosphonates (zoledronic acid (ZA), pamidronate, and clodronate) and denosumab. Results: A total of 44,800 patients with lung cancer and incident BM diagnosis were identified during the study period. Median age at the time of BM diagnosis was 67 years (25 th and 75 th percentile: 57-76), with 58.2% male (n = 26,058). The annual number of lung cancer patients with incident BM increased from 2,814 in 2004 to 3,829 in 2016, while the proportion of these patients receiving any BTA during the follow-up ranged from 25.2% to 34.8% annually. Clodronate and pamidronate were the common BTA prescriptions, whereas denosumab became the most frequently prescribed BTA after reimbursement by NHI since 2015. Among patients who initiated BTA after BM diagnosis (n = 10,879), the median time from BM diagnosis to BTA initiation ranged from 31 to 152 days by initial BTA type. More than half of them received more than one dose (56.3%, n = 6,126), with median numbers of doses received as 3, 4, 6 and 6 for ZA, pamidronate, clodronate and denosumab, respectively. Conclusions: A large population of patients with lung cancer were diagnosed with BM every year. However, overall, we observed only a small proportion of eligible patients receiving a BTA and a delayed initiation of BTA, indicating suboptimal treatment for lung cancer patients with BM in Taiwan.[Table: see text]
OTHR-42. Missing data tolerant integration of proteomic datasets enables the identification and characterization of brain cancer subtypes
Authors: Hannah Voss, Shweta Godbole, Simon Schlumbohm, Matthias Dottermusch, Yannis Schuhmann, Philipp Neumann, Hartmut Schlüter, Ulrich Schüller, Bojia Peng, Philip Barwikowski, Christoph Krisp, Julia E Neumann
Journal: Neuro-Oncology (2022)

Abstract Investigating the proteome can add a significant layer of information to manifold existing methylation, mutation, and transcriptome data on brain tumors as proteins represent the pharmacologically addressable phenotype of a disease. Small cohorts limit the usability and validity of statistical methods, and variable technical setups and high numbers of missing values make data integration from public sources challenging. Using a newly developed framework being able to reduce batch effects without the need for data reduction or missing value imputation, we show –based on in-house and publicly available datasets- successful integration of proteomic data across different tissue types, quantification platforms, and technical setups. Exemplarily, data of a Sonic hedgehog (Shh) medulloblastoma mouse model were analyzed, showing efficient data integration independent of tissue preservation strategy or batch. We further integrated batches of publicly available data of human brain tumors, confirming proposed proteomic cancer subtypes correlating with clinical features. We show that, missing value tolerant reduction of technical variances may be helpful to identify biomarkers, proteomic signatures, and altered pathways characteristic for molecular brain cancer subtypes.
Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study
Authors: Claire Daien, Marek Krogulec, Paul Gineste, Jean-Marc Steens, Laurence Desroys du Roure, Sophie Biguenet, Didier Scherrer, Julien Santo, Hartmut Ehrlich, Patrick Durez
Journal: Annals of the Rheumatic Diseases (2022)

Objective This phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy. Methods The primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission. Results ABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464. Conclusion ABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA. Trial registration name Phase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy. EUDRACT number: 2018-004677-27 Trial registration number NCT03813199 .
A phase II study, with a safety lead-in, to evaluate ATX-101, a peptide drug targeting PCNA, in advanced dedifferentiated liposarcoma and leiomyosarcoma.
Authors: Sminu Bose, Matthew Ingham, Shahnaz V. Singh-Kandah, Wendy Magana, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2022)

TPS11587 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of mesenchymal origin; leiomyosarcoma (LMS) and liposarcoma (LPS), two of the most common adult STS, are treated with first-line chemotherapy with objective response rates (ORRs) of 15-20%. There is an urgent need for novel therapeutics. ATX-101 is a small peptide comprised of a novel human AlkB homolog 2 proliferating cell nuclear antigen (PCNA) interacting motif termed APIM coupled to cellular and nuclear delivery domains. Via APIM, PCNA interacts with many cellular proteins important in the cellular stress and DNA damage responses, as well as intracellular signaling, apoptosis, metabolism, and anti-tumor immunity. In preclinical studies, ATX-101 demonstrated single-agent activity and potentiated other cytotoxic and targeted agents across multiple cancer models in vitro and in vivo, including LMS and LPS. In a phase I safety and pharmacokinetic study in solid tumors, ATX-101 was well tolerated and demonstrated prolonged disease stabilization in patients (pts) with heavily pretreated malignancies. This study will evaluate preliminary efficacy and further establish the safety profile of ATX-101 in advanced LMS and LPS. Methods: This is a single-arm, open-label, Simon 2-stage, phase II clinical trial of ATX-101 in pts with advanced LMS and LPS. Eligible pts have ECOG PS ≤2, progression on ≥1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive ATX-101 60 mg/m2 IV weekly in continuous 21-day cycles. The 1° endpoint is progression free rate at 12 weeks (PFR12). A Simon 2-stage design is used to evaluate for improvement in PFR12 of ≤ 30% (null hypothesis) versus ≥ 55% (alternative hypothesis). The design calls for 34 pts with a safety lead-in among the first 10 pts enrolled. If 15/34 meet the PFR12 endpoint, the treatment is promising. This design yields 85% power and 1-sided type I error of 5%. 2° endpoints include progression free survival, ORR, and safety. 10 pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating ATX-101’s effects on the immune microenvironment through multiplex immunohistochemistry, DNA damage response through whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, and intracellular signaling pathways by Western blot for AKT/mTOR components. The study opened to accrual 12/2021. Clinical trial information: NCT05116683.
3-D Printed prostate cancer model prior to Robotic-Assisted Radical Prostatectomy: Initial experience and a surgeon, patient, radiologist, and pathologist point of view
Authors: F. Vasconcelos Ordones, L.F. Takano De Araujo, L.F Fornazieri, B.A. Olivetti Artioli, P.K. Roberto Kawano, J.L. Amaro, K.R. Leite
Journal: European Urology (2022)
Prevalence of incidental pathogenic germline variants detected in cfDNA in patients with oncogene-driven non-small cell lung cancer.
Authors: Laura Mezquita, Leslie A. Bucheit, Juan Carlos Laguna, Belen Pastor, Cristina Teixido, Teresa Gorria, Victor Albarran-Artahona, Marta Garcia de Herreros, Roxana Reyes, Noemi Reguart, Nuria Vinolas, Ainara Arcocha, Joan Anton Puig-Butillé, Leylah Drusbosky, Iris Faull, Elena Castro, Jyoti D. Patel, Aleix Prat, Benjamin Besse
Journal: Journal of Clinical Oncology (2022)

10569 Background: Preliminary data has highlighted inherited predisposition to lung cancer (LC) related to certain pathogenic germline variant (PGV) in cancer predisposing genes, including patients (pts) with tumors harboring somatic driver oncogene alterations (alt); however, the frequency of PGV in LC is unknown. Liquid biopsy assays may be able to identify incidental PGV (iPGV) in pts with solid tumors at scale. Here, we report the prevalence of iPGV in genes predisposing to cancer in pts with advanced non-small cell LC (aNSCLC) relative to driver alt status. Methods: Genomic results were retrospectively queried from 31126 pts with aNSCLC who had Guardant360 testing as part of routine clinical care from 10/2020-12/2021. iPGVs were defined as being non-synonymous, non-VUS alt in selected genes known to increase lifetime cancer risk (Table) with variant allele frequency (VAF) &gt;30% and pathogenicity defined by a proprietary bioinformatics pipeline. Clinical factors such as age, gender, histology, and diagnosis status (new/progressing) were extracted from test requisition forms. The driver group included guideline-recommended and emerging somatic mutations (m) in EGFR/KRAS/BRAF/MET/HER2, fusions (f) in ALK/ROS1/RET/NTRK1-3 and amplifications (a) in HER2/MET. Results: Out of 31126, 720 (2.3%) of pts had predicted iPGV, of whom 54% were female, with a median age of 64 (22-100); most pts were newly diagnosed (66%). Among them, 92% of pts had iPGVs identified in the homologous recombination and repair (HRR) pathway, 3% in mismatch repair (MMR) pathway and 5% EGFR iPGVs. A total of 335 (47%) pts with iPGVs had somatic driver alt (Table): 20% of pts with iPGV had KRASm (n=144/720; 67 G12C), 12% EGFRm (n=87; 28 ex19del, 35 ex21(L858R)), 2.5% BRAFm (n=18), 2.5% METm ex14 skip (n=18), 0.1% HER2m (n=1), 0.8% ALKf (n=6), 0.1% ROS1f (n=1), 0.1% RETf (n=1), 0.1% HER2a (n=1), and 0.4% METa (n=3). ATM iPGVs were enriched in pts with driver alt. (45% driver vs 27% non-driver, p&lt;0.0001) while BRCA1 iPGVs were more frequently observed in pts without driver alt. (17% vs 8%, p&lt;0.0001). Distribution of other iPGVs was similar across driver/non-driver groups. Conclusions: In this large cohort, 2.3% of pts with aNSCLC were iPGV-carriers; 47% of pts had oncogene-driven tumors, particularly with KRAS, EGFR, BRAF and MET alt. iPGV and lung carcinogenesis need further evaluation to define the role of genetic predisposition in LC risk and to determine the highest risk individuals to explore screening and therapeutic strategies, such as in pts with other solid tumors. [Table: see text]